Method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition

ABSTRACT

The present invention provides uses of a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted, for the preparation of a medicament for the treatment, alleviation of symptoms of relieving, improving and preventing a cognitive disease, disorder or condition in a subject. Additionally, the invention provides use of said salt adducts for the preparation of medicaments for the improvement of cognitive functions in a healthy subject.

FIELD OF THE INVENTION

The present invention relates to methods of treating and/or relievingand/or improving and/or preventing a cognitive disease, disorder orcondition in a subject in need thereof using metadoxine and derivativesthereof or compositions comprising thereof.

BACKGROUND OF THE INVENTION

Alterations in cognitive function may lead to altered state ofconsciousness, or to altered cognitive function, and may manifest inmemory impairment, or learning disabilities, or any type of alteredfunction.

Attention deficit hyperactivity disorder (ADHD) is characterized bypervasive and impairing symptoms of inattention, hyperactivity, andimpulsivity. ADHD/ADD is one of the most thoroughly researched disordersin medicine. It has been associated with a broad range of negativeoutcomes for affected subjects and with serious financial burden tofamilies and society, which marks it as a major public health problem.

Amnesia is a condition which can be defined by loss of memory due tosome disturbing or appalling psychological experience, brain injury orchain of emotional events. There are different reasons and causes ofamnesia such as organic or functional reasons. Organic amnesia is causeddue to damage to the brain by external factors which can be due tophysical impacts like trauma or disease. Functional amnesia is due topsychological factors. There are many reasons which can be the cause ofamnesia-like phenomena: head injury, severe illness, high fever,seizures, emotional shock or hysteria, alcohol-related brain damage,drugs, stroke, Alzheimer's disease and brain surgery, any type ofmetabolic disease such as hepatic or uremic encephalopathy, any diseasethat altered blood flow in the brain, or altered neurotransmission inthe brain, or is the result of increase or decrease in any type ofmetabolite in the brains, any disease associated with accumulation ofamyloid in the brain, or with the alteration of electrical function, ormetabolic function, or any type of altered mechanism in the brain.

Fatigue is related to most lifestyle habits and mental healthconditions. The literature describes fatigue as a complex phenomenonthat represents decreased ability to perform or accomplish mental orphysical tasks or respond after extended activity as well as decreasedmotivation to perform tasks. The level of fatigue experienced by anindividual relates to past cumulative daily activity patterns and toperiods of sleep and activity. In summary, fatigue results from timespent on tasks, natural circadian factors, and inadequate sleep.Alertness, on the other hand, is the state of readiness andattentiveness achieved without artificial or natural enhancements.

Having difficulties with concentrating is a symptom that can arise fromboth physical and psychological or emotional problems. Symptoms of lackof or deficiency in concentration may or may not be associated withother memory-related symptoms such as forgetfulness. Physical medicalconditions that affect concentration include Lyme disease, whiplash, andvarious others. Psychological conditions that may impair concentrationinclude depression, certain anxiety disorders, and stress. Sleepdisorders such as insomnia or sleep apnea can also impair concentrationability.

Metadoxine is a pyridoxine-pyrrolidone carboxylate (also known aspyridoxol L,2-pyrrolidon-5 carboxylate or pyridoxine5-oxo-2-pyrrolidon-carboxylate) with significant alcohol scavengingproperties. Metadoxine has been used to treat acute alcoholintoxication, poisoning, and certain other acute alcohol syndromes(reviewed in Addolorato et al., Int. J. Immunopathol. Pharmacol. (2003)16:207-214). Long term data show that metadoxine is safe for use byhumans.

Metadoxine accelerates the elimination of alcohol from the blood andtissues, helping restore the functional structure of the liver andalleviate neuro-psychological disorders associated with chronic alcoholintoxication and related syndromes. In animal studies, metadoxineincreased plasma clearance and urinary excretion of ethanol, inhibitedthe increased production of fatty acid esters in the liver duringchronic alcohol intake, reduced oxidative stress and preventedglutathione depletion in hepatic tissues (Antonelli et al., Pharmacol.Res. Commun. (1984) 16:189-197). In the brain, metadoxine increased thelevel of GABA and acetylcholine in the frontoparietal cortex of guineapigs.

Metadoxine is an ion-pair between pyrrolidone carboxylate (PCA) andpyridoxine (vitamin B6) with the two compounds linked in a singleproduct by salification. The pairing with PCA synergistically increasesthe pharmacological activity of pyridoxine (see, e.g., U.S. Pat. No.4,313,952). Metadoxine is freely soluble in water and in gastric fluid.Oral absorption of the drug is fast with high bioavailability (60-80%).The half life of metadoxine in human serum is short (40-60 minutes)without appreciable differences between oral and intravenousadministration (Addolorato et al., supra; Lu Yuan et al., Chin. Med. J.2007 120(2) 160-168).

Metadoxine is marketed in several countries as a prescription drug inthe form of 500 mg tablets and 300 mg injections. Tablets contain 500 mgof metadoxine, microcrystalline cellulose and magnesium stearate.Ampoules contain 300 mg of metadoxine, sodium metabisulfite, EDTAsodium, methyl-p-hydroxybenzoate and water.

U.S. Pat. No. 6,541,043 describes a composition and method for treatingAttention Deficit/Hyperactivity Disorder (ADHD), the compositioncomprising dimethylaminoethanol (DMAE), together with a variety ofagents, inter alia vitamin B6, optionally with conventional drugs fortreating ADHD. WO03/003981 discloses compositions for thestructural/functional nutritional support for subjects with poor focus,concentration and/or memory, as well as subjects who subjectivelyexperience transient mental fatigue or poor cognitive function. Thesecompositions comprise, inter alia B-complex vitamins, including B6, andL-pyroglutamic acid, together with a large number of other ingredients.WO09/004,629 describes a method for decreasing or preventing symptoms oreffects of alcohol consumption comprising administration metadoxine.US20070248696 describes a composition for improving neuromuscularfacilitation, also known as “muscle memory,” and enhancing cognitivefunctions, such as memory and mental focus, in the form of a dietarysupplement that comprises, amongst many ingredients, also vitamin B6.US20090081179 discloses the use of polyunsaturated fatty acids and e.g.vitamin B6 amongst others, in treatment of patients suffering fromParkinson's disease, Huntington's chorea, epilepsy, schizophrenia,paranoia, depression, sleep disorders, impaired memory function,psychoses, dementia and ADHD. EP 511943 describes pyroglutamic acidderivatives as enhancers of learning processes and memory. The effect ofadministration of metadoxine on memory recovery was tested on abstinentchronic alcoholic. Vitamin B6 was administered to a control group ofsimilar patients. It was found that metadoxine helps recovery ofshort-term memory after 1-2 months of abstinence, and that its effectwas superior to that of vitamin B6 [Sinforiani et al., Clin. Trials J.,27(2): 103-111 (1990)]. WO2010/013242 discloses salt adducts comprisingat least one positively charged moiety being a pyridoxine or aderivative thereof and at least one carboxylated 5- to 7-membered lactamring, optionally additionally substituted, methods of their preparation,and pharmaceutical compositions and medicaments comprising them for thetreatment of diseases or disorders associated with or inflicted byalcohol consumption.

There exists a need for methods able to treat, alleviate the symptomsof, relieve, improve and prevent a cognitive disease, disorder orcondition, cognitive behavior and functioning, and maintain theseimprovements for prolonged duration.

It is an object of the invention to provide methods for treating suchcognitive disorders and deficiencies using metadoxine and derivativesthereof or compositions comprising thereof. It is another object of theinvention to provide compositions comprising metadoxine or derivativesthereof, for long-term treatment of cognitive deficiencies. These andother objects of the invention will become apparent as the descriptionproceeds.

SUMMARY OF THE INVENTION

The present invention is intended at solving one or more of the problemsreferred to above, by providing various methods for improving cognitiveperformance by administering a composition comprising metadoxine or aderivative thereof to a subject in need. Metadoxine and/or metadoxinederivatives compositions formulated for sustained or controlled release,optionally also including an immediate release component or a metadoxineor a metadoxine derivative, and methods for using such sustained orcontrolled release or combined metadoxine or metadoxine derivativesformulations of the invention, are also provided. The composition maycomprise metadoxine or metadoxine derivative formulated for sustainedrelease or controlled release. In some aspects, the compositionscomprising metadoxine or metadoxine derivatives may have a portion ofthe metadoxine or metadoxine derivatives formulated for sustained orcontrol led release and a portion of the metadoxine or metadoxinederivatives formulated for immediate release.

In one of its aspect, the invention provides a method for the treatment,alleviation of symptoms of, relieving, improving and preventing acognitive disease, condition or disorder, in a healthy subject or apatient in need, said method comprising administering to said subject aneffective amount of metadoxine or a derivative thereof.

In another aspect the invention provides a method for the treatment,alleviation of symptoms of, relieving, improving and preventing acognitive disease, disorder or condition in a subject, said methodcomprising administering to said subject an effective amount of a saltadduct comprising at least one positively charged moiety being apyridoxine or a derivative thereof and at least one carboxylated 5- to7-membered lactam ring, optionally additionally substituted.

In a further aspect the invention provides a method for the improvementof cognitive functions in a healthy subject, said method comprisingadministering to said subject an effective amount of a salt adductcomprising at least one positively charged moiety being a pyridoxine ora derivative thereof and at least one carboxylated 5- to 7-memberedlactam ring, optionally additionally substituted.

When referring to “metadoxine”, it should be understood to encompass thesalt adduct pyridoxine L-2-pyrrolidone-5-carboxylate. Metadoxine is asalt of the corresponding anion of L-2-pyrrolidone-5-carboxylic acid(L-2-pyroglutamic acid) (1) and the protonated derivative of pyridoxine(vitamin B6) (2), having the following structures:

When referring to a “metadoxine derivative” it should be understood toencompass any other salt adduct comprising at least one positivelycharged moiety being a pyridoxine or a derivative thereof and at leastone carboxylated 5- to 7-membered lactam ring, optionally additionallysubstituted.

In all embodiments of the invention said positively charged moiety is acompound of formula (I):

wherein R₁ is straight or branched C₁-C₆ alkyl; R₂ is selected from —OH,straight or branched C₁-C₆ alkoxy, and straight or branched C₁-C₆alkoxycarbonyl; R₃ and R₄ are each independently selected from formyl,straight or branched C₁-C₆ alkyl optionally substituted by at least onehalogen, amine, hydroxy, C₁-C₆ alkoxy, thiol and C₁-C₆ alkoxycarbonyl.

In further embodiments of the invention said carboxylated lactam ring isselected from the group consisting of:

wherein R₆ is selected from H, straight or branched C₁-C₆ alkyloptionally substituted by at least one halogen, straight or branchedC₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl, cycloalkyl, aryl andheteroaryl optionally substituted by a C₁-C₆ alkyl; R₇, R₈, R₉, R₁₀ R₁₁,R₁₂, R₁₃ and R₁₄ are each independently selected from H, straight orbranched C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, aryl andheteroaryl optionally substituted by at least one group selected fromC₁-C₆ alkyl, halogen, amino, cyano, nitro, thiol, C₁-C₆ alkoxy,aminocarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ carboxyalkyl, C₁-C₆alkoxycarbonylalkyl and amidino.

In yet further embodiments of the invention said salt adduct is selectedfrom the following:

When referring to a cognitive disease, disorder or condition alleviated,relieved, improved or prevented by a method of the invention, it shouldbe understood to encompass at least one of the following non-limitingconditions: Attention Deficit/Hyperactivity Disorder (ADHD/ADD),impaired memory (Amnesia), impaired wakefulness, mental fatigueconditions (including disease related fatigue), Shift Work SleepDisorder, Narcolepsy, Obstructive Sleep Apnea/Hypopnea Syndrome,Depression, Substance dependence (including for example addictivesubstances), Parkinson's disease, Schizophrenia, Poor concentration, andPoor focus, or any combination thereof.

In another one of its aspects, the invention provides a method for thetreatment, alleviation of symptoms of, relieving, improving andpreventing a neurobehavioral disorder, such as for example ADHD and/orADD, in a patient in need or in a health subject experiencing symptomsassociated with or connected to a permanent or temporary neurobehavioraldisorder such as ADHD and/or ADD, said method comprising administeringto said subject an effective amount of metadoxine or a derivativethereof.

When referring to a neurobehavioral disorder alleviated, relieved,improved or prevented by a method of the invention, it should beunderstood to encompass at least one of the following non-limitingconditions: Attention Deficit Disorder (ADD) Attention DeficitHyperactivity Disorder (ADHD), Poor concentration, and Poor focus, orany combination or symptoms thereof.

The methods of the invention may further improve wakefulness in subjects(at any age, such as for example pediatric, adolescent or adultsubjects) who experience excessive sleepiness due to one of thefollowing non-limiting diagnosed sleep disorders: obstructive sleepapnea/hypopnea, shift work sleep disorder and narcolepsy.

Furthermore, a cognitive disease, disorder or condition alleviated,relieved, improved or prevented by a method of the invention mayadditionally include any condition associated with learningdisabilities, impairment of memory, cognitive dysfunction, alteration ofcognitive function, including Alzheimer's disease, or any type ofencephalopathy, including uremic and hepatic encephalopathy.

In addition, a neurobehavioral disorder alleviated, relieved, improvedor prevented by a method of the invention may additionally include anycondition associated any symptoms associated or connected with aneurobehavioral disorder such as for example learning disabilities,impairment of memory, cognitive dysfunction, alteration of cognitivefunction, etc.

Accordingly, in any of the various embodiments of the methods of theinvention described above, the composition may comprise metadoxine ormetadoxine derivatives formulated for immediate release, sustainedrelease, controlled release, or a combination of any of the foregoing.

When referring to a cognitive function it should be understood toencompass at least one of the following non-limiting list: temporary orlong term learning disabilities, temporary or long term impairment ofmemory, temporary or long term cognitive dysfunction, temporary or longterm alteration of cognitive function, temporary or long termconcentration impairment, temporary or long term focus impairment,temporary or long term impaired wakefulness, temporary or long termmental fatigue conditions, temporary or long term Shift Work SleepDisorder, or any combination thereof.

It should be understood that when referring to an improvement in thecognitive functions in a healthy subject, it is meant to encompass anychange (minor or significant) in the cognitive condition of a subject.Specifically said improvement may be noticeable in at least one of thefollowing non-limiting list of conditions: temporary or long termlearning disabilities, temporary or long term impairment of memory,temporary or long term cognitive dysfunction, temporary or long termalteration of cognitive function, temporary or long term concentrationimpairment, temporary or long term focus impairment, temporary or longterm impaired wakefulness, temporary or long term mental fatigueconditions, temporary or long term Shift Work Sleep Disorder, or anycombination thereof.

In certain other aspects, the invention provides a method for increasingthe mean t_(max) of metadoxine or metadoxine derivatives in the blood ofa subject comprising administering a metadoxine or metadoxinederivatives composition of the invention formulated for sustainedrelease or controlled release, optionally including a portion of themetadoxine or metadoxine derivatives formulated for immediate release.

In certain aspects, the invention provides a use of any one of thecompositions of the invention for the manufacture of a therapeuticand/or pharmaceutical composition and/or medicament useful forpracticing each of the methods of the invention as described herein,e.g., for treatment, alleviation of symptoms of, relieving, improvingand preventing a cognitive disease, disorder or condition in healthypatients or patients suffering from Attention Deficit/HyperactivityDisorder (ADHD/ADD), impaired memory (Amnesia), mental fatigueconditions, poor concentration, and poor focus. The subject may be achild, an adolescent, an adult or an elderly or aged person.

The invention also relates to any condition associated with learningdisabilities, impairment of memory, any alteration of cognitivefunction, including Alzheimer's disease, related to alterations in bloodflow, sclerosis, amyloid deposition, alteration of neurotransmitters inthe brain, metabolic alterations such as the accumulation of ammonia,any type of encephalopathy, including uremic and hepatic encephalopathy,or any type of altered functions due to altered levels of any substance.

Alterations in cognitive function may lead to altered state ofconsciousness, or to altered cognitive function, and may manifest inmemory impairment, or learning disabilities, or any type of alteredfunction.

In any of the various embodiments of metadoxine or metadoxinederivatives compositions described herein (e.g., metadoxine ormetadoxine derivatives formulated for immediate release, sustainedrelease, controlled release, or a combination of any of the foregoing),the metadoxine may consist of, or comprise a physiologically compatiblemetadoxine derivative, as described herein.

The invention will be described in more detail on hand of the appendeddrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the invention and to see how it may be carriedout in practice, embodiments will now be described, by way ofnon-limiting example only, with reference to the accompanying drawings,in which:

FIG. 1 shows a graph of the rate of release of certain metadoxinecompositions of the present invention as described in Example 1. Thegraph illustrates the difference between an immediate releaseformulation and a slow release formulation of metadoxine. Metadoxine (%)released vs. time (hours).

FIG. 2 illustrates the rates of release of immediate-release formulationcompared to release from slow-release tablets.

DETAILED DESCRIPTION OF EMBODIMENTS

In the first aspect the invention provides a method for the treatment,alleviation of symptoms of, relieving, improving and preventing acognitive disease, disorder or condition in a subject, said methodcomprising administering to said subject an effective amount of a saltadduct comprising at least one positively charged moiety being apyridoxine or a derivative thereof and at least one carboxylated 5- to7-membered lactam ring, optionally additionally substituted.

In a further aspect the invention provides a method for the improvementof cognitive functions in a healthy subject, said method comprisingadministering to said subject an effective amount of a salt adductcomprising at least one positively charged moiety being a pyridoxine ora derivative thereof and at least one carboxylated 5- to 7-memberedlactam ring, optionally additionally substituted.

In another one of its aspects the invention provides, a use of a saltadduct comprising at least one positively charged moiety being apyridoxine or a derivative thereof and at least one carboxylated 5- to7-membered lactam ring, optionally additionally substituted, for thepreparation of a medicament for the treatment, alleviation of symptomsof, relieving, improving and preventing a cognitive disease, disorder orcondition in a subject.

In a further aspect the invention provides, a use of a salt adductcomprising at least one positively charged moiety being a pyridoxine ora derivative thereof and at least one carboxylated 5- to 7-memberedlactam ring, optionally additionally, for the preparation of amedicament for the improvement of cognitive functions in a healthysubject.

In all embodiments of the invention said positively charged moiety is acompound of

Wherein R₁ is straight or branched C₁-C₆ alkyl; R₂ is selected from —OH,straight or branched C₁-C₆ alkoxy, and straight or branched C₁-C₆alkoxycarbonyl; R₃ and R₄ are each independently selected from formyl,straight or branched C₁-C₆ alkyl optionally substituted by at least onehalogen, amine, hydroxy, C₁-C₆ alkoxy, thiol and C₁-C₆ alkoxycarbonyl.

In other embodiments of the invention, said carboxylated lactam ring isselected from the group consisting of:

wherein R₆ is selected from H, straight or branched C₁-C₆ alkyloptionally substituted by at least one halogen, straight or branchedC₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl, cycloalkyl, aryl andheteroaryl optionally substituted by a C₁-C₆ alkyl; R₇, R₈, R₉, R₁₀ R₁₁,R₁₂, R₁₃ and R₁₄ are each independently selected from H, straight orbranched C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, aryl andheteroaryl optionally substituted by at least one group selected fromC₁-C₆ alkyl, halogen, amino, cyano, nitro, thiol, C₁-C₆ alkoxy,aminocarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ carboxyalkyl, C₁-C₆alkoxycarbonylalkyl and amidino.

In yet further embodiments of the invention, said carboxylated lactamring is a compound of formula (II):

and said positively charged moiety is compound (2):

wherein R₆, R₇, R₈, R₉ and R₁₀ are as defined above.

In other embodiments, said carboxylated lactam ring is compound (1):

and said positively charged moiety is a compound of formula (I):

wherein R₁, R₂, R₃ and R₄ are as defined above.

In other embodiments, R₁ is a C₁-C₆ alkyl and R₂, R₃ and R₄ are asdefined above.

In further embodiments, R₂ is selected from —OH and C₁-C₆ alkoxy; andR₁, R₃ and R₄ are as defined above.

In further embodiments, R₃ is —CH₂R₁₅, wherein R₁₅ is selected from—C₁-C₆ alkoxy, —OH and —NH₃ ⁺; and R₁, R₂ and R₄ are as defined above.

In other embodiments, R₄ is selected from formyl and —CH₂R₁₆, whereinR₁₆ is selected from —C₁-C₆ alkoxy and —OH; and R₁, R₂ and R₃ are asdefined above.

In further embodiments, R₁ is —CH₃, R₂ is —OH, R₃ and R₄ are both—CH₂OH.

In yet other embodiments, said carboxylated lactam ring is a compound offormula (II):

wherein R₆, R₇, R₈, R₉ and R₁₀ are as defined above. In someembodiments, R₆ is C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆ alkyl.

In further embodiments, said carboxylated lactam ring is a compound offormula (III):

and said positively charged moiety is a compound of formula (I):

wherein R₁, R₂, R₃, R₄, R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ are as definedabove.

In further embodiments, said carboxylated lactam ring is a compound offormula (IV):

and said positively charged moiety is a compound of formula (I):

wherein R₁, R₂, R₃, R₄, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ andR₁₄ are as defined above.

In yet further embodiments, said positively charged moiety is compound(2):

In some embodiments of the invention, said salt adduct is selected fromthe following:

In further embodiments, said cognitive disease, disorder or condition isselected from Attention Deficit/Hyperactivity Disorder (ADHD/ADD),impaired memory (Amnesia), impaired wakefulness, mental fatigueconditions, Shift Work Sleep Disorder, Narcolepsy, Obstructive SleepApnea/Hypopnea Syndrome, poor concentration, and poor focus or anycombination thereof.

In further embodiments, said cognitive disease, disorder or condition isselected from learning disabilities, impairment of memory, cognitivedysfunction, alteration of cognitive function, including Alzheimer'sdisease, or any type of encephalopathy, including uremic and hepaticencephalopathy.

In yet further embodiments, said cognitive disease, disorder orcondition is a neurobehavioral disease, disorder or condition.

In other embodiments, said neurobehavioral disease, disorder orcondition is selected from Attention Deficit Hyperactivity Disorder(ADHD), Attention Deficit Disorder (ADD), impaired memory, poorconcentration, and poor focus.

In further embodiments, said cognitive disease, disorder or condition isselected from Attention Deficit Disorder (ADD) or Hyperactivity Disorder(ADHD/ADD), impaired memory (Amnesia), impaired wakefulness, mentalfatigue conditions, Shift Work Sleep Disorder, Narcolepsy, ObstructiveSleep Apnea/Hypopnea Syndrome, poor concentration, and poor focus or anycombination thereof.

In other embodiments, said cognitive function selected from temporary orlong term learning disabilities, temporary or long term impairment ofmemory, temporary or long term cognitive dysfunction, temporary or longterm alteration of cognitive function, temporary or long termconcentration impairment, temporary or long term focus impairment,temporary or long term impaired wakefulness, temporary or long termmental fatigue conditions, temporary or long term Shift Work SleepDisorder, or any combination thereof.

In yet further embodiments, said subject is a child, an adolescent, anadult, or an elderly person.

In all embodiments of the invention, said salt adduct is formulated in asustained-, delayed or controlled-release dosage form.

In further embodiments of the invention, said salt adduct is formulatedin a sustained-, delayed or controlled-release dosage form combined witha salt adduct formulated in an immediate or burst effect dosage form.

In further embodiments of the invention, said salt adduct is formulatedto deliver up to 0.1-1000 mg/kg body weight/day of said salt adduct,preferably 1-400 mg/kg body weight of said salt adduct, in a single doseadministration or portion thereof. In other embodiments said salt adductis formulated to deliver up to 100-700 mg/kg body weight/day of saidsalt adduct.

In other embodiments of the invention, said salt adduct is formulatedtogether with at least one additional pharmaceutically active agent.

In yet further aspects of the invention, there is provided a salt adductcomprising at least one positively charged moiety being a pyridoxine ora derivative thereof and at least one carboxylated 5- to 7-memberedlactam ring, optionally additionally substituted, for use in thetreatment, alleviation of symptoms of, relieving, improving andpreventing a cognitive disease, disorder or condition in a subject.

In another aspect the invention provides, a salt adduct comprising atleast one positively charged moiety being a pyridoxine or a derivativethereof and at least one carboxylated 5- to 7-membered lactam ring,optionally additionally, for use in the improvement of cognitivefunctions in a healthy subject.

DEFINITIONS

For convenience, certain terms employed in the specification, examples,and appended embodiments, are collected here. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “including” is used herein to mean, and is used interchangeablywith, the phrase “including but not limited to”.

The term “or” is used herein to mean, and is used interchangeably with,the term “and/or,” unless context clearly indicates otherwise.

The term “such as” is used herein to mean, and is used interchangeably,with the phrase “such as but not limited to”.

The term “prophylactic” or “therapeutic” treatment refers toadministration to a subject of one or more of the compositions of theinvention. If it is administered prior to clinical manifestation of theunwanted condition (e.g., clinical or other unwanted state of the hostanimal) then the treatment is prophylactic, i.e., it contributes toprevention of, i.e., protection of the subject against developing anunwanted condition, whereas if administered after manifestation of anunwanted condition, the treatment is therapeutic (i.e., it is intendedto diminish, ameliorate or prevent progression of the unwanted conditionor side effects there from).

The term “therapeutic effect” refers to a local or systemic effect inanimals, particularly mammals, and more particularly humans, caused by apharmacologically active substance or substances. The term thus meansany substance intended for use in diagnosis, cure, mitigation, treatmentor prevention of disease or in the enhancement of desirable physical ormental development and conditions in an animal or human. The term“therapeutically effective amount” means that amount of such a substancethat produces some desired local or systemic effect at a reasonablebenefit/risk ratio applicable to any treatment. In certain embodiments,a therapeutically-effective amount of a compound or composition willdepend on its therapeutic index, solubility, and the like. For example,certain metadoxine or metadoxine derivatives formulations of the presentinvention may be administered in a sufficient amount to produce areasonable benefit/risk ratio applicable to a selected treatment, as maybe determined by the skilled artisan.

The term “effective amount” refers to the amount of a therapeuticreagent that when administered to a subject in an appropriate dose andregimen produces at least one desired result.

A “subject” or “patient” to be treated by a method of the invention maymean either a human or non-human animal, preferably a mammal. The term“subject” as used herein may refer to a healthy individual, or a subjectsuffering any cognitive problems. The terms “subject” and “healthysubject” and “subject in need” and “patient in need” as used hereinexclude subjects under alcohol influence following alcohol consumptionof any form, alcoholics (alcohol addicts), and abstinent alcoholics.

The terms “cognitive” or “cognitive function” or “cognitive problems” orcognitive disorders” or “cognitive malfunction” or “cognitive disease,disorder or condition” and the like, may be used herein interchangeablyand as used herein may be taken to mean any function of cognition,including but not limited to Attention Deficit/Hyperactivity Disorder(ADHD/ADD), impaired memory (Amnesia), mental fatigue conditions, poorconcentration, poor focus, as well as in any condition associated withlearning disabilities, impairment of memory, any alteration of cognitivefunction, including Alzheimer's disease, related to alterations in bloodflow, sclerosis, amyloid deposition, alteration of neurotransmitters inthe brain, metabolic alterations such as the accumulation of ammonia,any type of encephalopathy, including uremic and hepatic encephalopathy,or any type of altered functions due to altered levels of any substance.

In this connection it may be mentioned that cognitive dysfunctionincludes any conditions resulting from, inter alia, altered blood flowto whole or part of the brain such as in stroke; altered acid basebalance; altered in electrolytes; alteration (increase or decrease) ofthe level of any metabolite, e.g. urea or ammonia; deposition of anysubstrate such as amyloid in any part of the brain such as in AlzheimerDisease or Parkinson's Disease; alteration in any part of the immunesystem whether peripheral or central, that affect the brain, such as inmultiple sclerosis or different types of lupus erythematosus; changes inlevel or function of any cytokine or chemokine; effect/s of drug/sdirected towards or targeted to the brain, or affecting the brain in aindirect manner; alterations in neurotransmitters; and any alterationsof nerves or synapses in the brain.

The terms “neurobehavioral” or “neurobehavioral function” or“neurobehavioral problems” or “neurobehavioral disorders” or“neurobehavioral malfunction” and the like, may be used hereininterchangeably and as used herein may be taken to mean any function ofcognition, including but not limited to Attention Deficit/HyperactivityDisorder (ADHD/ADD), impaired memory, poor concentration, poor focus, aswell as in any condition associated with learning disabilities,impairment of memory, or any symptoms associated or connected there fromsuch as for example poor performance in social (home, community, etc.),educational (class, playground, etc.) environments.

The present invention relates to any of the known ADHD subtypes:

(i) Predominantly hyperactive-impulsive: for which most symptoms are inthe hyperactivity-impulsivity categories, and some symptoms ofinattention are present, although inattention may still be present tosome degree,(ii) Predominantly inattentive: the majority of symptoms are in theinattention category and fewer symptoms of hyperactivity-impulsivity arepresent, although hyperactivity-impulsivity may still be present to somedegree; Children with this subtype are less likely to act out or havedifficulties getting along with other children. They may sit quietly,but they are not paying attention to what they are doing. Therefore, thechild may be overlooked, and parents and teachers may not noticesymptoms of ADHD.(iii) Combined hyperactive-impulsive and inattentive: some of thesymptoms of inattention and some symptoms of hyperactivity-impulsivityare present.

Inattentive type symptoms may include:

-   -   Subjects may be easily distracted, miss details, forget things,        and frequently switch from one activity to another    -   Subjects may have difficulty focusing on one thing    -   Subjects may become bored with a task after only a few minutes,        unless doing something enjoyable    -   Subjects may have difficulty focusing attention on organizing        and completing a task or learning something new    -   Subjects may have trouble completing or turning in homework        assignments, often losing objects (e.g., pencils, toys,        assignments) needed to complete tasks or activities    -   Subjects do not seem to listen when spoken to    -   Subjects may daydream, become easily confused, and move slowly    -   Subjects may have difficulty processing information as quickly        and accurately as others    -   Subjects may struggle to follow instructions.

Predominantly hyperactive-impulsive type symptoms include:

-   -   Subjects may be fidget and squirm in their seats    -   Subjects may talk nonstop    -   Subjects may dash around, touching or playing with anything and        everything in sight    -   Subjects may have trouble sitting still during dinner, school,        and story time    -   Subjects may be constantly in motion    -   Subjects may have difficulty doing quiet tasks or activities.

Additional manifestations of primarily impulsivity may include:

-   -   Subjects may be very impatient    -   Subjects may be blurt out inappropriate comments, show their        emotions without restraint, and act without regard for        consequences    -   Subjects may have difficulty waiting for things they want or        waiting their turns in games

As used herein the term “salt adduct” is meant to encompass a saltproduct of a direct addition of two or more distinct ions, wherein theoverall charge of the salt adduct is zero. In certain embodiments, thesalt adduct comprises one positively charged moiety having a singlepositive charge functional group (i.e., the positively charged moiety ischarged with +1 net charge) and one negatively charged moiety having asingle negative charge functional group (i.e., the negatively chargedmoiety is charged with −1 net charge). In certain embodiments, the saltadduct comprises one positively charged moiety having two positivelycharged functional groups, which may be the same or different (i.e., thepositively charged moiety is charged with +2 net charge) and twonegatively charged moieties, which may be the same or different, andeach having a single negative charged functional group (i.e., eachnegatively charged moiety is charged with −1 net charge). In certainembodiments, the salt adduct comprises two positively charged moieties,which may be the same or different, having each one positively chargedfunctional group (i.e., each positively charged moiety is charged with+1 net charge) and one negatively charged moiety, having two negativelycharged functional groups, being the same or different (i.e., thenegatively charged moiety is charged with −2 net charge). In certainembodiments, the salt adduct comprises a positively charged moietycharged with +n net charge (originating from one or more positivelycharged functional groups, which may be the same or different), and anegatively charge moiety having −n (originating from one or morenegatively charged functional groups, which may be the same ordifferent) net charge, wherein n is an integer which may be equal to 1,2, 3, 4, 5 or 6.

As used herein, a “positively charged moiety of a salt adduct” of theinvention is the corresponding acid of pyridoxine, or any derivativethereof. In certain embodiments, the positive charge of the positivelycharged moiety stems from the protonated basic nitrogen atom ofpyridoxine (as for example in compound (2)) or any derivative thereof(such as for example compounds of formula (I)). In certain embodiments,the positively charged pyridoxine derivative is substituted with apositively charged functional group such as for example —NH₃ ⁺, —CH₂NH₃⁺, —NH₂R⁺, —NHR₂ ⁺ (wherein each R is independently a C₁-C₆ alkyl),which may, in some embodiments, be present in addition to the positivelycharged protonated basic aromatic nitrogen atom in the pyridine ring.

As used herein, a “carboxylated 5- to 7-membered lactam ring” of a saltadduct of the invention, is meant to encompass a γ-lactam, δ-lactam orε-lactam rings, having a negatively charged carboxylate group (—COO⁻)substituted thereto. In certain embodiments, said carboxylate group issubstituted at the lactam ring carbon atom adjacent to the amidenitrogen. In another embodiment said carboxylated lactam ring is aL-2-pyrrolidone-5-carboxylate (compound (1)). In other embodiments saidcarboxylate group is substituted on any position of the lactam ring. Incertain embodiments, said carboxylated 5- to 7-membered lactam ring maybe substituted by another substituent at any position on the lactamring. The term “halogen” as used herein means F, Cl, Br or I.

The term “C₁-C₆ alkyl” as used herein represents a saturated, branchedor straight hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms.Typical C₁₋₆ alkyl groups include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, hexyl, isohexyl and the like.

The term “C₂-C₆ alkenyl” as used herein represents a branched orstraight hydrocarbon chain having 2, 3, 4, 5 or 6 carbon atoms and atleast one double bond positioned between any two carbons of the chain.Examples of such groups include, but are not limited to, ethenyl,1-propenyl, 2-propenyl, isopropenyl, 1,3-butadienyl, 1-butenyl,2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl and the like.

The term “C₂-C₆ alkynyl” as used herein represents a branched orstraight hydrocarbon chain having 2, 3, 4, 5 or 6 carbon atoms and atleast one triple bond positioned between any two carbons of the chain.Examples of such groups include, but are not limited to, ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl,1-hexynyl, 2-hexynyl and the like.

The term “C₁-C₆ alkoxy” as used herein refers to the radical —O—C₁₋₆alkyl, wherein C₁₋₆ alkyl is as defined above. Representative examplesare methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy,tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.

The term “C₁-C₆ alkylthio” as used herein refers to the radical —S—C₁₋₆alkyl, wherein C₁₋₆ alkyl is as defined above. Representative examplesare methylthio, ethylthio, isopropylthio, n-propylthio, butylthio,pentylthio and the like.

The term “cycloalkyl” as used herein represents a monocyclic,carbocyclic group having 3, 4, 5, 6, 7 or 8 carbon atoms, but may alsoinclude heteroatoms such as N, O and/or S. Representative examples arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl and the like.

The term “aryl” as used herein is intended to include carbocyclicaromatic ring systems such as phenyl, biphenylyl, naphthyl, anthracenyl,phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and the like.Aryl is also intended to include the partially hydrogenated derivativesof the carbocyclic systems enumerated above. Non-limiting examples ofsuch partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl,1,4-dihydronaphthyl and the like.

The term “heteroaryl” as used herein refers to ring systems in which atleast one ring is an aromatic ring in which at least one atom is anon-carbon atom, either substituted or non-substituted, where thenon-carbon atom may be, for example, a nitrogen, sulfur or oxygen atom.

The term “C₁-C₆ alkoxycarbonyl” as used herein refers to the radical—C(O)O—C₁₋₆ alkyl, wherein C₁₋₆ alkyl is as defined above.

The terms “C₁-C₆ alkoxy” and “C₁-C₆ alkylthio” as used herein refers tothe radicals C₁₋₆—O— and C₁₋₆—S—, respectively, wherein C₁₋₆ alkyl is asdefined above.

The term “hydroxyl” as used herein refers to the radical —OH. As usedherein the term “thiol” refers to the radical —SH. As used herein theterm “formyl” refers to the radical —COH. As used herein the term“cyano” refers to the radical —CN. As used herein the term “nitro”refers to the radical —NO₂.

The term “amine” as used herein refers to —NH₃ or any primary (—NH₂R),secondary (—NHR₂), tertiary (—NR₃) or quarternary amines (—NR₄ ⁺),wherein each R may be the same or different and independently selectedfrom H, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl as defined hereinabove.

The term “C₁-C₆ carboxyalkyl” as used herein refers to the radical—CO—(C₁-C₆ alkyl), wherein C₁₋₆ alkyl is as defined above.

The term “aminocarbonyl” as used herein refers to the radical —CONR₂,wherein each of groups R is independently selected from H, C₁-C₆ alkyl,C₁-C₆ alkenyl, C₁-C₆ alkynyl as defined herein above.

The term “alkoxycarbonylalkyl” as used herein refers to the radical—OCO—(C₁-C₆alkyl), wherein C₁₋₆ alkyl is as defined above.

The term “amidino” as used herein refers to the radical —C(═NH)—NH₂.

The term “optionally substituted” as used herein means that the moietiesreferred to are either unsubstituted or substituted with one or more ofthe substituents specified. When the moieties referred to aresubstituted with more than one substituent the substituents may be thesame or different.

Such substituents can include, for example, a halogen, a hydroxyl, acarbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl),a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),an alkoxyl, an alkylthio, an acyloxy, a phosphoryl, a phosphate, aphosphonate, an amino, an amido, an amidine, an imine, a cyano, a nitro,an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, asulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or anaryl or heteroaryl moiety.

It should be understood that moieties of a salt adduct of the inventionmay contain each at least one chiral center, and thus may exist in, andbe isolated as, any stereoisomer thereof including, enantiomers,diastereomers or any mixtures thereod including, but not limited toracemic mixtures. The present invention includes any possiblestereoisomer (e.g. enantiomers, diastereomers), any mixtures thereofincluding, but not limited to, racemic mixtures, of any of theindividual moieties of a salt adduct of the invention. Where theherein-described processes for the preparation of each of the moietiesof a salt adduct of the invention give rise to mixtures ofstereoisomers, these isomers may be separated by conventionaltechniques, such as preparative chromatography. The moieties of a saltadduct of the invention may be each prepared in any mixture of possiblestereoisomers thereof, including but not limited to racemic mixturesthereof, or individual stereoisomers (e.g. enantiomers, diastereomers)may be prepared either by enantiospecific synthesis or by chiralchromatographic separation of a racemate. Whenever referring to aminoacids, the invention should be understood to encompass natural andnon-natural amino acids or any derivative thereof.

The term “non-natural amino acid” as used herein refers herein to aminoacids, or any derivative thereof, that are not among the amino acidswhich are the building blocks of proteins having L as well asD-configurations, while “natural amino acids”, refer to amino acids orany derivative thereof, which are the building blocks of proteins,having L as well as D-configurations.

Table 1 depicts several examples of salt adducts of the presentinvention.

TABLE 1 Salt Structural formula No.

IId

IIe

IIId

IIa

IIb

IIc

Throughout this specification, the word “comprise” or variations such as“comprises” or “comprising” will be understood to imply the inclusion ofa stated integer or groups of integers but not the exclusion of anyother integer or group of integers.

The term “bio-available” means that at least some amount of a particularcompound is present in the systemic circulation. Formal calculations oforal bioavailability are described in terms of an F value (“Fundamentalsof Clinical Pharmacokinetics,” John G. Wegner, Drug IntelligencePublications; Hamilton, Ill. 1975). F values are derived from the ratioof the concentration of the parent drug in the systemic circulation(e.g., plasma) following intravenous administration to the concentrationof the parent drug in the systemic circulation after administration by anon-intravenous route (e.g., oral). Therefore, oral bioavailabilitywithin the scope of the present invention contemplates the ratio or Fvalue of the amount of parent drug detectable in the plasma after oraladministration compared to intravenous administration.

The term “treating” or “treatment” refers to mitigating, improving,relieving or alleviating at least on symptom of a condition, disease ordisorder in a mammal, such as a human, or the improvement of anascertainable measurement associated with a condition, disease ordisorder. Treatment as used herein also encompasses treatment of healthyindividuals.

The term “acceptable derivative” with respect to metadoxine ormetadoxine derivatives refers to any salt, conjugate, ester, complex orother chemical derivative of metadoxine or any of the moietiescomprising the same, which, upon administration to a subject, is capableof providing (directly or indirectly) metadoxine or a metabolite orfunctional residue thereof, or measurable metadoxine activity. The term“physiologically compatible metadoxine derivative” may be usedinterchangeably herein with the term “acceptable derivative” and refersto a functional, active, pharmaceutically acceptable derivative ofmetadoxine.

The term “excipient” refers to an inactive substance used as a carrierfor the active ingredient in a formulation.

The term “controlled release” refers to any formulation which deliversan agent at a controlled rate for an extended time and is designed toachieve a desired agent level profile.

The term “sustained release” is used in its conventional sense to referto a formulation that provides for gradual release of an active materialover an extended period of time, which in certain embodiments may alsofurther result in substantially constant blood levels over an extendedtime period, i.e., controlled release.

The term “immediate release” is used in its conventional sense to referto a formulation that provides for non delayed or controlled release ofan active material upon administration.

The term “half-life” of a substance is the time it takes for a substanceto lose half of its pharmacologic, physiologic, or other activity.Biological half-life is an important pharmacokinetic parameter and isusually denoted by the abbreviation t_(in).

The term “non-invasive” refers to modes of treatment which do notpuncture the skin.

The term “non-chronic administration” may be used interchangeably hereinwith the term “acute administration” and refers to giving a measured ornon-measured quantity or portion of a medication to a subject on anon-regular basis. Non-chronic administration may be a single dosetreatment or a multiple dose treatment, and may optionally be given overtime. Typically but not always, a non-chronic administration is given totreat or prevent a non-chronic condition. Certain chronic conditions mayalso benefit from non-chronic administration of a metadoxine ormetadoxine derivatives composition described herein.

The term “chronic administration” refers to giving a measured quantityof a medication on a regular basis to a subject. In some embodiments,chronic administration is to treat or prevent one or more chronicconditions, problems or diseases. Chronic diseases have one or more ofthe following characteristics: they are permanent, leave residualdisability, are caused by nonreversible pathological alteration, requirespecial training of the patient for rehabilitation, or may be expectedto require a long period of supervision, observation, or care.

The term “single dose treatment” refers to giving a measured quantity ofa medication to be taken at one time. It is given to treat non-chronicconditions on an irregular basis, depending on personal need.

The term “t_(max)” refers to the time to peak concentration. Calculationof time at which maximum concentration occurs after a single doseadministration is performed according to the formula:

$t_{\max} = {\frac{2.303}{\lambda_{\alpha} - \lambda_{z}}\log \frac{\lambda_{\alpha}}{\lambda_{z}}}$

where λ_(α) and λ_(z) are the apparent absorption and elimination rateconstants, respectively.

Methods of Treatment and Prevention Using Metadoxine or MetadoxineDerivatives Compositions

In certain embodiments, the present invention provides a method forimprovement of cognitive function and/or behavior in healthy patients orpatients suffering from Attention Deficit/Hyperactivity Disorder(ADHD/ADD), impaired memory (Amnesia), mental fatigue conditions, poorconcentration, and poor focus comprising administering a compositioncomprising metadoxine or a derivative thereof. In certain suchembodiments, the method comprises non-chronic administration of acomposition comprising metadoxine or a derivative thereof.

In certain embodiments, the present invention provides a method forincreasing the mean t_(max) of metadoxine or metadoxine derivatives inthe blood of a subject for improving or treating cognitive condition asherein defined, comprising administering a composition comprisingmetadoxine or a derivative thereof, and especially wherein thecomposition comprises metadoxine or a derivative thereof formulated inwhole or in part for sustained or controlled release. In certain suchembodiments, the method comprises non-chronic administration of acomposition comprising metadoxine or a derivative thereof formulated inwhole or in part for sustained or controlled release. In certainembodiments of the invention, the mean t_(max) of metadoxine ormetadoxine derivative in the blood of a subject is increased by 50%,100%, 150%, 200%, 300%, 400%, 500% or greater than 500%.

In certain embodiments, the application provides a method for increasingthe half-life (t_(1/2)) of metadoxine or a metadoxine derivative in theblood or serum of a subject, for improving or treating cognitivecondition as herein defined, comprising administering a compositioncomprising metadoxine or a derivative thereof, and especially whereinthe composition comprises metadoxine or a derivative thereof formulatedin whole or in part for sustained release or controlled release,optionally including a portion of the metadoxine or a metadoxinederivative formulated for immediate release. In certain embodiments ofthe invention, the t_(1/2) of metadoxine or metadoxine derivative in theblood or serum of a subject is increased by 50%, 100%, 150%, 200%, 300%,400%, 500% or greater than 500%.

In certain of the above described methods of the invention, themetadoxine or derivative thereof may be formulated for immediate releaseupon administration to the subject. In certain of the above describedmethods of the invention, the metadoxine or derivative thereof may beformulated for sustained and/or controlled release, and may optionallybe formulated to have both immediate release and sustained and/orcontrolled release characteristics upon administration to the subject.In certain embodiments, metadoxine or a derivative thereof is formulatedfor non-chronic administration. Metadoxine or metadoxine derivativeformulations used by the invention are described in more detail below.

Metadoxine or Metadoxine Derivatives Formulations and AdministrationRegimens

In certain embodiments, the present invention provides a compositioncomprising metadoxine or a derivative thereof formulated for sustainedand/or controlled release when administered to a subject for improvingor treating cognitive condition as herein defined for improving ortreating cognitive condition as herein defined.

In certain embodiments, the present invention provides a compositioncomprising metadoxine or a derivative thereof wherein a portion of themetadoxine or derivative is formulated for sustained and/or controlledrelease and a portion of the metadoxine or derivative is formulated forimmediate release when administered to a subject for improving ortreating cognitive condition as herein defined.

In certain embodiments, effective serum levels of the active ingredientare achieved within from about 10 to about 20 or 30 or 40 or 50 or 60,90 minutes, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h followingmetadoxine or metadoxine derivative administration. In certainembodiments, effective serum levels of the active ingredient in saidsubject are achieved within from about 5 to about 20 or 30 or 40 or 50or 60, 90 minutes, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 hfollowing metadoxine or metadoxine derivative administration. In certainembodiments, effective serum levels of the active ingredient areachieved within from about 20 to about 20 or 30 or 40 or 50 or 60, 90minutes, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h followingmetadoxine or metadoxine derivative administration. In certainembodiments, effective serum levels of the active ingredient areachieved within about 5, 10, 15, 20, 30, 40, 50 or 60, 90 minutes, 2 h,3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h.

The present inventors have developed innovative approaches for theadministration of metadoxine or metadoxine derivative based on enteral(via the digestive tract) and/or parenteral (other routes than digestivetract) routes (WO2009/004629). These approaches provide for a rationaldesign of delivery systems with desired properties based on themeticulous selection of the carrier, e.g. appropriatesurfactants/co-surfactants composition or micro/nano particles (such asliposomes or nano-liposomes) entrapping the active ingredients, or otheradditives or excipients, for the delivery system of interest.

The enteral delivery systems may be designed for oral administration(tablets, sachets, lozenges, capsules, gelcaps, drops, or otherpalatable form) or rectal administration (suppository or (mini) enemaform).

In addition, the delivery system of interest may be in liquid form, forexample a drop solution, syrup. Furthermore, the delivery system ofinterest may be in form of a beverage or food article. Thus, the activeingredient/s used by the invention may be comprised in a beverage,particularly soft drinks like juices, nectars, water, sparkling waterand other sparkling drinks, shakes, milk shakes and other milk-baseddrinks, and the like. Liquid preparations may also be in the form ofconcentrated syrups, for diluting with water or sparkling water.Alternatively, the active ingredient/s may be comprised in foodarticles, such as snack bars, health bars, biscuits, cookies, sweets,confectionery products, ice creams, ice lollies, and the like.

Still further, the delivery system may be a food or beverage articlecomprising a physiologically active pyridoxine derivative, particularlypyridoxol L,2-pyrrolidon-5 carboxylate (metadoxine). In certainembodiments, consumption of the food or beverage article of theinvention may lead to achievement of serum levels of the activeingredient within from about 10 to about 40-60 minutes followingconsumption thereof. Examples may be sweets, chocolate, candies andcandy bars, energy bars, ice creams, pastry products and the like.

The parenteral ways of administration include subcutaneous, transferal(diffusion through the intact skin), transmucosal (diffusion through amucous membrane), sublingual, buccal (absorbed through cheek neargumline) administration, or administration by inhalation. In certainembodiments, the compositions used by the invention are not administeredby invasive modes of treatment (i.e., are non-invasive). In certainembodiments, the metadoxine or metadoxine derivative compositions arenot administered by intravenous injection.

In certain embodiments, compositions used by the invention are deliveredas a microcrystalline powder or a solution suitable for nebulization;for intravaginal or intrarectal administration, pessaries,suppositories, creams or foams. A preferred formulation is a formulationfor oral administration. Another preferred formulation is for topicaladministration. Another preferred formulation is for transmucosaladministration, sublingual, buccal (absorbed through cheek near gumline)administration, administration by inhalation or ocular administration,e.g., in eye drops.

Administration of metadoxine or metadoxine derivative for medical usesrequires safe and efficient delivery systems. The present inventionprovides delivery systems for safe delivery of a variety of substancesdue to their special physico-chemical features, particularly directabsorption, by non-invasive means, and consequent avoidance of sideeffects. The delivery systems significantly enhance efficiency andquality of metadoxine or metadoxine derivative absorption based on itsunique physicochemical features, which enables lower concentrations oramounts of active substance to be delivered to a subject in abiologically active form. The delivery systems of the invention providefor the direct access of the active substance to the tissues and thusprovide immediate or near-immediate effects of metadoxine or metadoxinederivative to the treated subject.

Accordingly, in certain embodiments, the present invention uses anon-invasive pharmaceutical delivery system for the improvedadministration of a physiologically active pyridoxine, particularlypyridoxol L,2-pyrrolidon-5 carboxylate (metadoxine), or aphysiologically acceptable derivative thereof, comprising as the activeingredient said physiologically active pyridoxine in a suitable carrier.In certain embodiments, serum levels of the active ingredient areachieved within from about 10 to about 40-60 minutes followingadministration.

In another embodiment, the invention employs a non-invasivepharmaceutical delivery system for the improved administration of aphysiologically active pyridoxine derivative, particularly pyridoxolL,2-pyrrolidon-5 carboxylate (metadoxine), for use in improvement ofcognitive behavior in a subject in need thereof, comprising as theactive ingredient said pyridoxine derivative, in a suitable carrier. Incertain embodiments, serum levels of said active ingredient are achievedwithin from about 10 to about 40-60 minutes following administration.

In certain embodiments, the drug delivery systems employed by theinvention may be designed for oral, nasal, ocular, rectal, subcutaneous,transferal, transmucosal, sublingual, buccal or inhalationadministration. The drug delivery systems may provide the activesubstance in a controlled release mode. In certain embodiments, the drugdelivery systems of the invention may further comprise at least oneadditional pharmaceutically active agent.

The delivery systems used by the invention may generally comprise abuffering agent, an agent that adjusts the osmolarity thereof, andoptionally, one or more pharmaceutically acceptable carriers, excipientsand/or additives as known in the art. Supplementary pharmaceuticallyacceptable active ingredients can also be incorporated into thecompositions. The carrier can be solvent or dispersion mediumcontaining, for example, water, ethanol, polyol (for example, glycerol,propylene glycol, and liquid polyethylene glycol, and the like),suitable mixtures thereof, and vegetable oils. The proper fluidity canbe maintained, for example, by the use of a coating, such as lecithin,by the maintenance of the required particle size in the case ofdispersion and by the use of surfactants.

As used herein “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art.

Except as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic composition iscontemplated. It is contemplated that the active agent can be deliveredby any pharmaceutically acceptable route and in any pharmaceuticallyacceptable dosage form.

Oral forms include, but are not limited to, tablets, capsules, pills,sachets, lozenges, drops, powders, granules, elixirs, tinctures,suspensions, syrups, and emulsions. Also included are oralrapid-release, time controlled-release, and delayed-releasepharmaceutical dosage forms. The active drug components can beadministered in a single dosage form or in separate dosage forms to beadministered together or independently. The active drug components canbe administered in a mixture with suitable pharmaceutical diluents,excipients or carriers (collectively referred to herein as “carrier”),materials suitably selected with respect to the intended form ofadministration.

Where the delivery system is for oral administration and is in the formof a tablet or capsule or the like, the active drug components can becombined with a non-toxic pharmaceutically acceptable inert carrier suchas lactose, starch, sucrose, glucose, modified sugars, modifiedstarches, methylcellulose and its derivatives, dicalcium phosphate,calcium sulfate, mannitol, sorbitol, and other reducing and non-reducingsugars, magnesium stearate, stearic acid, sodium stearyl fumarate,glyceryl behenate, calcium stearate and the like. For oraladministration in liquid form, the active drug components can becombined with non-toxic pharmaceutically acceptable inert carriers suchas ethanol, glycerol, water and the like. When desired or required,suitable binders, lubricants, disintegrating agents and coloring andflavoring agents can also be incorporated into the mixture. Stabilizingagents such as antioxidants, propyl gallate, sodium ascorbate, citricacid, calcium metabisulphite, hydroquinone, and 7-hydroxycoumarin canalso be added to stabilize the dosage forms. Other suitable compoundscan include gelatin, sweeteners, natural and synthetic gums such asacacia, tragacanth, or alginates, carboxymethylcellulose, polyethylene,glycol, waxes and the like.

Additional suitable pharmaceutically acceptable carriers that may beused in these pharmaceutical compositions include, but are not limitedto, ion exchangers, alumina, aluminum stearate, magnesium stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat. In some embodiments, thepharmaceutically acceptable carrier is magnesium stearate. Additionalpharmaceutical excipients commonly accepted and used are found in, forexample, Remington's Pharmaceutical Sciences (Gennaro, A., ed., MackPub., 1990).

For purposes of parenteral administration, solutions in suitable oilsuch as sesame or peanut oil or in aqueous propylene glycol can beemployed, as well as sterile aqueous solutions of the correspondingwater-soluble salts. Such aqueous solutions may be suitably buffered, ifnecessary, and the liquid diluent first rendered isotonic withsufficient saline or glucose. These aqueous solutions are especiallysuitable for intravenous, intramuscular, subcutaneous andintraperitoneal injection purposes. In this connection, the sterileaqueous media employed are all readily obtainable by standard techniqueswell-known to those skilled in the art. Methods of preparing variouspharmaceutical compositions with a certain amount of active ingredientare known, or will be apparent in light of this disclosure, to thoseskilled in this art.

The half-life of metadoxine in human serum is very short. Lu Yuan et al.(Chin. Med. J 2007 120(2) 160-168), showed a mean half life of about 0.8hour. A way of prolonging serum levels of active moiety is byadministering the material in a sustained-release formulation. Becausemetadoxine is freely soluble in water and in various biological fluids,it is difficult to sustain its release and prolong its absorption time.Therefore, it was unexpected that sustained release could be achieved. Acontrol release dosage form of metadoxine or metadoxine derivative maybe based on a predetermined gradual release of the active ingredient inthe biological fluids, resulting in a sustained action with smallfluctuations of the plasma level over a prolonged period of time.

In certain embodiments, the delivery system used by this invention maybe administered in controlled release formulations. In certainembodiments, the method of administration will be determined by theattending physician or other person skilled in the art after anevaluation of the subject's condition and requirements. An embodiment ofthe method of the present invention is to administer the therapeuticcompound described herein in a sustained release form. Any controlled orsustained release method known to those of ordinary skill in the art maybe used with the compositions and methods of the invention such as thosedescribed in Langer, Science 249(4976):1527-33 (1990). Such methodcomprises administering a sustained-release composition, a suppository,or a coated implantable medical device so that a therapeuticallyeffective dose of the composition of the invention is continuouslydelivered to a subject of such a method. Sustained release may also beachieved using a patch designed and formulated for the purpose. Thecomposition of the invention may be delivered via a capsule which allowssustained-release of the agent over a period of time. Controlled orsustained-release compositions include formulation in lipophilic depots(e.g., fatty acids, waxes, oils). Also comprehended by the invention areparticulate compositions coated with polymers (e.g., poloxamers orpoloxamines). Sustained release formulae or devices, or any topicalformulations, may additionally contain compositions to stabilize thecomposition or permeate physiological barrier such as skin or mucousmembrane. Exemplary additional components may include anyphysiologically acceptable detergent, or solvent such as, for example,dimethylsulfoxide (DMSO).

In all embodiments of the invention, methods and uses of the inventionmay employ a composition comprising a salt adduct as defined by theinvention formulated as a single dose. Said single dose formulation maybe an immediate release formulation, a burst formulation, a prolongedrelease formulation, a sustained release formulation or any othercontrolled release formulation known to a person skilled in the art.

In other embodiments of the methods and uses of the invention, acomposition comprising a salt adduct defined by the invention may be acombined dosage formualtion, wherein different types of formulations areadministered to a subject, i.e. any combination of an immediate releaseformulation, a burst formulation, a prolonged release formulation, asustained release formulation or any other controlled releaseformulation known to a person skilled in the art, given either in asingle dose or in separate doses given seperately, concomitantly orsequentially wherein the gap of time between administration of separatedosages is defined based on the condition and severity of disease ordisorder of a subject or the physical condition of said subject.

In some embodiments a composition used by the methods of the inventionare formulated as combined dosage forms, wherein at least one dosagefrom of a suit adduct defined by the invention is in an immediaterelease form and at least one doage form of a salt adduct defined by theinvention (being the same or different from the salt adduct formulatedin the immediate release formulation) is formulated as a controlled(slow and/or sustained) release formulation. In other embodiments theweight ratio of a salt adduct as defined by the invention comprised insaid at least one immediate release formulation and at least onecontrolled release formulation may be 1:1, 1:2, 2:1, 3:2, 2:3, 1:3, 3:1,4:1, 1:4, 5:2, 2:5, 1:5, 5:1. When employing such combined dosage formsin a method or use of the invention, said at least one immediate releaseform and at least one controlled release form of a salt adduct definedabove, may be administered to a subject seperately, concomitantly,sequentially, concurrently, consequetively and so forth. In someembodiments said at least one immediate release form is administeredinitially. In other embodiments said at least one controlled releaseformulation is administered initially.

In certain embodiments, the metadoxine or metadoxine derivative incompositions of the invention may be formulated for sustained orcontrolled release over a period of at least 0.5, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11 or 12 hours. In certain embodiments, the metadoxine ormetadoxine derivative in compositions used by the invention may beformulated for sustained or controlled release over a period of about0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours. In certainembodiments, the metadoxine or metadoxine derivative in compositionsused by the invention may be formulated for sustained or controlledrelease over a period of between about 0.5 or 1 or 2 or 3 or 4 hours andabout 5, 6, 7, 8, 9, 10, 11 or 12 hours. In certain embodiments, themetadoxine or metadoxine derivative in compositions used by theinvention may be formulated for sustained or controlled release over aperiod of between about 5 or 6 or 7 or 8 hours and about 9, 10, 11 or 12hours.

In certain embodiments, the metadoxine or metadoxine derivative incompositions used by the invention may be in immediate, fast of burstrelease form.

In certain embodiments, the metadoxine or metadoxine derivative incompositions used by the invention may be formulated to release up to 5,10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,99, 99.5 or 100% of the total metadoxine or metadoxine derivative inabout 0.5, 1, 2, 3, 4, 5, 6, 7 or 8 hours. In certain embodiments, themetadoxine or metadoxine derivative in compositions used by theinvention may be formulated to release not less than 5, 10, 15, 20, 25,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99, 99.5 or 100%of the total metadoxine or metadoxine derivative in about 0.5, 1, 2, 3,4, 5, 6, 7 or 8 hours.

In certain embodiments, the metadoxine or metadoxine derivative incompositions used by the invention may be in a combination of sustainedor slow release and immediate or fast release forms. In certainembodiments, the relative proportion of sustained or slow releasemetadoxine or metadoxine derivative to immediate or fast releasemetadoxine or metadoxine derivative is, e.g., 1 to 99, 5 to 95, 10 to90, 15 to 85, 20 to 80, 25 to 75, 30 to 70, 35 to 65, 40 to 60, 45 to55, 50 to 50, 55 to 45, 60 to 40, 65 to 35, 70 to 30, 75 to 25, 80 to20, 85 to 15, 90 to 10, 95 to 5, or 99 to 1.

In certain embodiments, a polymeric material is used to sustain orcontrol the release of metadoxine or metadoxine derivative. In certainembodiments, the type of polymeric material and the amount of which isused, has a strong influence on the rate of release of metadoxine ormetadoxine derivative from the product of the present invention.Examples of polymers include both hydrophobic and hydrophilic polymers.Examples of hydrophobic polymers include, but are not limited to, ethylcellulose and other cellulose derivatives, fats such as glycerolpalmito-stereate, beeswax, glycowax, castorwax, carnaubawax, glycerolmonostereate or stearyl alcohol, hydrophobic polyacrylamide derivativesand hydrophobic methacrylic acid derivatives, as well as mixtures ofthese polymers. Hydrophilic polymers include, but are not limited to,hydrophilic cellulose derivatives such as methyl cellulose,hydroxypropylmethyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethyl cellulose, sodium carboxymethylcellulose andhydroxyethyl methyl-cellulose polyvinyl alcohol, polyethylene,polypropylene, polystyrene, polyacrylamide, ethylene vinyl acetatecopolymer, polyacrylate, poly-urethane, polyvinylpyrrolidone,polymethylmethacrylate, polyvinyl acetate, polyhydroxyethylmethacrylate, as well as mixtures of these polymers. Furthermore, anymixture of one or more hydrophobic polymer and one or more hydrophilicpolymer could optionally be used.

In certain embodiments, a polymeric material to be used in compositionsof or used by the invention is microcrystalline cellulose such as“Avicel PH 101” manufactured by FMC BioPolymer's.

In certain embodiments, a polymeric material to be used in compositionsof or used by the invention is hydroxypropyl methyl-cellulose such as“Metholose”, produced by Shin-Etsu Chemical Co.

In certain embodiments, a polymeric material to be used in compositionsof or used by the invention is ethyl cellulose such as “Ethocel™”,manufactured by The Dow Chemical Company.

In certain embodiments, a polymeric material to be used in compositionsof or used by the invention is an acrylic polymer such as “EudragitRS™”, produced by Rohm GmbH.

In certain embodiments, a polymeric material to be used in compositionsof or used by the invention is a colloidal silicone dioxide such as“Aerosil™”, manufactured by Degussa.

In certain embodiments, a polymeric material to be used in compositionsof or used by the invention is a poly(vinyl acetate) such as “KollicoatSR”, manufactured by BASF.

In certain embodiments, a polymeric material to be used in compositionsof or used by the invention is an ethyl acetate and vinyl acetatesolution such as “Duro-Tak”, manufactured by Delasco Dermatologic Lab &Supply, Inc.

In certain embodiments, the composition of or used by the inventioncomprises or consists essentially of Formula 1. Formula 1 comprises orconsists essentially of 100-3000 mg metadoxine or metadoxine derivativeand 5-20,000 mg Metholose.

In certain embodiments, the composition of or used by the inventioncomprises or consists essentially of Formula 2. Formula 2 comprises orconsists essentially of 100-3000 mg metadoxine or metadoxine derivativeand 5-7000 mg Ethocel E10™.

In certain embodiments, the composition of or used by the inventioncomprises or consists essentially of Formula 3. Formula 3 comprises orconsists essentially of 100-3000 mg metadoxine or metadoxine derivativeand 5-20,000 mg Eudragit RS™

In certain embodiments, the compositions of or used by the inventioncomprise or consist essentially of about 250, 300, 400, 500, 600, 700,800, or 900 mg to about 1000, 1500, 2000, 2500 or 3000 mg metadoxine ormetadoxine derivative. In certain embodiments, the compositions of orused by the invention comprise or consist essentially of about 5, 100,500, or 1000 mg to about 2000, 4000, 10,000, 15,000, or 20,000 mg AvicelPH 101™. In certain embodiments, the compositions of or used by theinvention comprise or consist essentially of about 25, 50, 100, 150,200, 250, 300, 350, 400, 450, 500, 550 or 600 mg to about 650, 700, 750,800, 850, 900, 950, 1000, 5000, 10,000, 15,000 or 20,000 mg of apolymeric material. In certain embodiments, the polymeric material isMetholose, Ethocel E10™ or Eudragit RS™. In certain embodiments,Metholose comprises or consists essentially of between 1 and 90% of theformulation, preferably between 5 and 70%. In certain embodiments,Ethocel™ comprises or consists essentially of between 1 and 30% of theformulation, preferably between 2 and 20%. In certain embodiments,Eudragit™ comprises or consists essentially of between 1 and 90% of theformulation, preferably between 5 and 70%.

In certain embodiments, delivery systems of or used by the inventioncomprise delivery devices. In certain embodiments, the compositions ofor used by the invention are delivered by an osmotic process at acontrolled rate such as by an osmotic pump. The system may beconstructed by coating an osmotically active agent with a ratecontrolling semipermeable membrane. This membrane may contain an orificeof critical size through which agent is delivered. The dosage form aftercoming into contact with aqueous fluids, imbibes water at a ratedetermined by the fluid permeability of the membrane and osmoticpressure of the core formulation. This osmotic imbibition of waterresults in formation of a saturated solution of active material withinthe core, which is dispensed at controlled rate from the deliveryorifice in the membrane.

In certain embodiments, the compositions of or used by the invention aredelivered using biodegradable microparticles. In certain embodiments,the system to prepare microparticles consists of an organic phasecomprised of a volatile solvent with dissolved polymer and the materialto be encapsulated, emulsified in an aqueous phase. In certainembodiments, the biodegradable polymers that can be used for themicroparticle matrix, comprises polylactic acid (PLA) or the copolymerof lactic and glycolic acid (PLAGA). The PLAGA polymer degradeshydrolytically over time to its monomeric components, which are readilyremoved from the body through natural metabolism.

The preparation of or used by the present invention may also contain anabsorption enhancer and other optional components. Examples ofabsorption enhancers include, but are not limited to, cyclodextrins,phospholipids, chitosan, DMSO, Tween, Brij, glycocholate, saponin,fusidate and energy based enhancing absorption equipment.

Optional components present in the dosage forms include, but are notlimited to, diluents, binders, lubricants, surfactants, coloring agents,flavors, buffering agents, preservatives, stabilizing agents and thelike.

Diluents, also termed “fillers” include, for example, dicalciumphosphate dihydrate, calcium sulfate, lactose, cellulose, kaolin,mannitol, sodium chloride, dry starch, hydrolyzed starches, silicondioxide, colloidal silica, titanium oxide, alumina, talc,microcrystalline cellulose, and powdered sugar. For administration inliquid form, the diluents include, for example, ethanol, sorbitol,glycerol, water and the like.

Binders are used to impart cohesive qualities to the formulation.Suitable binder materials include, but are not limited to, starch(including corn starch and pregelatinzed starch), gelatin, sugars(including sucrose, glucose, dextrose, lactose and sorbitol),polyethylene glycol, waxes, natural and synthetic gums, e.g., acacia,tragacanth, sodium alginate, celluloses, and Veegum, and syntheticpolymers such as polymethacrylates and polyvinylpyrrolidone.

Lubricants are used to facilitate manufacture; examples of suitablelubricants include, for example, magnesium stearate, calcium stearate,stearic acid, glyceryl behenate, and polyethylene glycol.

Surfactants may be anionic, cationic, amphoteric or nonionic surfaceactive agents, with anionic surfactants preferred. Suitable anionicsurfactants include, but are not limited to, those containingcarboxylate, sulfonate and sulfate ions, associated with cations such assodium, potassium and ammonium ions. Particularly preferred surfactantsinclude, but are not limited to long alkyl chain sulfonates and alkylaryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodiumsulfosuccinates, such as sodium bis-(2-ethylhexyl)-sulfosuccinate; andalkyl sulfates such as sodium lauryl sulfate.

Stabilizing agents such as antioxidants, include, but are not limitedto, propyl gallate, sodium ascorbate, citric acid, calciummetabisulphite, hydroquinone, and 7-hydroxycoumarin.

If desired, the compositions of or used by the invention may alsocontain minor amounts of nontoxic auxiliary substances such as wettingor emulsifying agents, preservatives, and the like.

Any of the compositions of or used by the invention may be used alone orin combination with one or more additional therapeutic agents, for theimprovement of cognitive behavior. Examples of additional therapeuticagents are: amphetamines, methylphenidate HCl, dexmethylphenidatehydrochloride, atomoxetine, reboxetine, fluoxatine, sertraline,paroxetine, fluoroxamine, citalopram, venlafaxine, bupropion, nefazodoneand mirtazapine.

The amount of both the compound and the additional therapeutic agentthat may be combined with the carrier materials to produce a singledosage form will vary depending upon the host treated and the particularmode of administration. Preferably, the compositions of this inventionshould be formulated so that a dosage of between 0.1-1 g/kg bodyweight/day, preferably 0.1-300 mg/kg body weight, can be administered.The dose of the compound depends on the condition and the illness of thepatient, and the desired daily dose. In human therapy, the oral dailydose is preferably 10-3000 mg. These doses are administered in unitdosage forms, which may be divided into 2-3 smaller doses for each dayin certain cases, especially in oral treatment.

In certain embodiments, the compositions of the present invention mayact synergistically in combination with each other and may further actsynergistically in the presence of an additional therapeutic agent.Therefore, the amount of compound(s) and additional therapeutic agent(s)in such compositions will be less than that required in a monotherapyutilizing only that therapeutic agent. In such compositions a dosage ofbetween 0.1-1 g/kg bodyweight/day of the additional therapeutic agentcan be administered.

Use of Metadoxine or Metadoxine Derivative to Prepare TherapeuticCompositions

In certain embodiments, the present invention provides a use ofmetadoxine or metadoxine derivative (including a functional,physiologically acceptable derivative of metadoxine) in the manufactureof a therapeutic composition useful for administering to a subject forimprovement of cognitive function or treatment and/or prevention ofcognitive disorders or malfunction according to any one of the methodsof the invention as described herein.

EXAMPLES

The following examples are intended to be illustrative of the disclosedinvention. The examples are non-limiting, and the skilled artisan willrecognize that other embodiments are within the scope of the presentinvention. Where not otherwise noted, methods were performed usingtechniques that would be understood by one of ordinary skill in the art.

Example 1 Metadoxine Release from Various Formulations

Metadoxine was formulated at various ratios of immediate release andslow release according to Table 1:

TABLE 1 Metadoxine formulations Formulation % Immediate No. of testedNo. Dosage Release % Slow Release patients 1  700 mg 30 70 3 2 1400 mg30 70 3 3 1190 mg 60 40 6 4 2100 mg 30 70 6

The above mentioned formulations were given to fasted healthy patients.Blood samples were collected following a predetermined time schedule inorder to characterise formulation absorption and elimination. Theresults are presented in FIG. 1.

FIG. 1 shows that Metadoxine reaches maximal concentration immediatelyafter about 0.5 hour and may remain in the blood for up to about 7hours. After singe administration in healthy Caucasian subjects,dose-linearity was demonstrated for C_(max) and AUC over the dose rangeof 700 to 2100 mg.

TABLE 2 Mean Pharmacokinetic Parameters of Metadoxine 700 mg, 1400 mgand 2100m after a Single Administration to Healthy Caucasian AdultsPharma- cokinetic Dual Extended Release Formulation of MetadoxineParameter 700 mg 1400 mg 2100 mg C_(max)  4.8 (4.5-6.3)  11.2 (8.0-12.8) 17.7 (15.2-22.3) (ng/mL) AUC_(0-∞) 8.29 (8.02-8.44) 54.49 (41.18-69.42)75.74 (56.99-98.34) (ng · h/ mL) t_(1/2) (h) 1.00 (0.81-1.30)  1.40(0.82-1.78)  1.22 (1.02-1.53)

Example 2 Metadoxine Formulation for Improvement of CognitivePerformance of ADHD/ADD Patients

38 ADHD/ADD adult patients (age 18-45) of ADHD unit of the Geha MentalHealth Center (Israel) were tested.

A total of four tablets were administered to each patient:

-   -   Two tablets of immediate release (IR) formulation (defined in        Table 3) and    -   Two tablets of slow release (SR) formulation (defined in Table        4).

The total dose of metadoxine administered was 1400 mg, in dual (combinedimmediate and slow) release formulation.

TABLE 3 Parameters of IR Drug Product Batch Strength 245 mg MetadoxineAppearance Concave round off-white tablets Diameter 8 mmDissolution >75% in 45 min Excipients Polyvinylpyrrolidone (PVP),Cellulose, Silicone Dioxide, Magnesium Stearate % excipients of total30%

TABLE 4 Parameters of SR Drug Product Strength 455 mg MetadoxineAppearance Concave round off-white tablets Diameter 11.5 mm Dissolution82.8% in 8 hours Excipients Ethyl Cellulose (EC),Hydroxypropylmethylcellulose (HPMC), Silicone Dioxide, MagnesiumStearate % excipients 15% of total

Tests at inclusion included selection of patients, and included clinicaldiagnosis by DSM IV, psychiatric examination, WURS & ASRSquestionnaires, TOVA (Test of Variables of Attention) score, Wechsler(Wechsler Adult Intelligence Scale) subtests, BDI (Beck DepressionInventory) and STAI (State-Trait Anxiety Inventory) questionnaire. Morethan one week after the inclusion, the participants were given a singledose of Metadoxine SR (1400 mg) and after 90 minutes performed again theWechsler subtests and the TOVA test.

The TOVA is a computerized test developed to assess attention andimpulsivity in normal and clinical populations. Main outcome measuresfor the TOVA are the Omission Standard Score (SS; inattention measure)the Commission Standard Score (SS; measure of impulse control), theResponse Time (RT) SS, the Variability in RT SS, and overall ADHD SS (acomposite score of the previous submeasures).

The Primary outcome measure was the ADHD Score, TOVA Omission, TOVACommission, TOVA RT and TOVA Variability analysed as Standard Score in %compared to the patient's prior performance of the TOVA test atbaseline. Secondary outcome measures were Subtests from Weschler: Digitspan, Symbol Search, Digit symbol.

Results:

TABLE 5 Results of TOVA (Test of Variables of Attention ContinuousPerformance Test) Baseline Post-medication ADHD Score (n = 34)* Mean−5.18 [−25.30 +4.29]  −1.77 [−13.9 +6.29] Δ (% of improvement vs Δ =+3.41 (+65.8%) Baseline) p-value p < 0.001 Omission Score (n = 38) Mean77.45 [40 109]  90.34 [40 109] Δ (% of improvement vs Δ = +12.89(+16.6%) Baseline) p-value p < 0.03 Commission Score (n = 38) Mean 98.16[40 121] 105.11 [48 123] Δ (% of improvement vs Δ = +6.95 (+7.1%)Baseline) p-value p < 0.01 RT Time (n = 38) Mean 88.87 [40 131]  99.89[45 135] Δ (% of improvement vs Δ = +11.02 (+12.4%) Baseline) p-value p< 0.02 RT Var (n = 38) Mean 62.42 [40 123]  86.5 [40 137] Δ (% ofimprovement vs Δ = +24.18 (+38.6%) Baseline) p-value p < 0.001 *Norms:ADHD Score >−1.8, Omission, Commission, Response Time and VariabilityScores: 85-115

The results of the TOVA test indicate statistically significantimprovement in all TOVA parameters those related to inattention (numberof omissions, greater stability in Response Time and decrease in overallADHD score) and those related to impulsivity (number of commissions).

TABLE 6 Results of Wechsler subtests Baseline Post-medication CorrectSymbols (n = 38) Mean 34.53 [18 59] 37.92 [22 57] Δ (improvement vsBaseline) Δ = +3.39 p-value p < 0.002 Symbol Search (n = 38) Mean 74.60[54 119] 81.76 [61 112] Δ (improvement vs Baseline) Δ = +7.16 p-value p< 0.001 Digits forwards (n = 38) Mean 10.00 [5 14] 10.71 [7 14] Δ(improvement vs Baseline) Δ = +0.71 p-value p < 0.03 Digits backwards (n= 38) Mean  6.97 [3 13]  7.84 [2 14] Δ (improvement vs Baseline) Δ =+0.87 p-value p < 0.01 Total Digit (n = 38) Mean 16.97 [9 26] 18.55 [1027] Δ (improvement vs Baseline) Δ = +1.58 p-value p < 0.002

The results of the Wechsler subtests confirmed the ability of Metadoxineto improve cognitive functions in the ADHD Adult population.

Discussion:

The comparison of the results for the overall ADHD score obtained withMetadoxine SR formulation of the invention with baseline scores, givenin Table 7 below, shows an improvement in ADHD Standard Score of about+90% versus baseline.

TABLE 7 Comparisons of ADHD Score (patients treated with Metadoxine)Comparison (1) Baseline (3) Metadoxine 1400 mg Mean 95% Confidence n =12 Difference Std Error p value¹ Interval (3) −4.417* 1.283 0.026 −8.28−0.55 (1) +8.103* 1.866 0.007 2.48 13.73 (3) +3.687 NS 1.883 0.258 −1.999.37 (1) +4.417* 1.866 0.026 0.55 8.28 *the mean difference issignificant at the 0.05 level ¹adjustment for multiple comparisons:Bonferroni

Example 3 Metadoxine Formulation for Improvement of CognitivePerformance of ADHD/ADD Patients

Ten adult ADHD subjects patients (age 18-45) of ADHD unit of the GehaMental Health Center (Israel) were tested.

A single tablet was administered to each patient comprising 1400 mg doseof DER Metadoxine.

The total dose of metadoxine administered was 1400 mg, in dual extendedrelease formulation.

Tests at inclusion included selection of patients, and included clinicaldiagnosis by DSM IV, psychiatric examination, WURS & ASRSquestionnaires, TOVA (Test of Variables of Attention) score, Wechsler(Wechsler Adult Intelligence Scale) subtests, BDI (Beck DepressionInventory) and STAI (State-Trait Anxiety Inventory) questionnaire.

After the inclusion, the participants were given a single dose ofMetadoxine DER (1400 mg) and perfomed the TOVA test after the followingtime periods: 90 minutes, 4 hours and 7 hours.

The TOVA is a computerized test developed to assess attention andimpulsivity in normal and clinical populations. Main outcome measuresfor the TOVA are the Omission Standard Score (SS; inattention measure)the Commission Standard Score (SS; measure of impulse control), theResponse Time (RT) SS, the Variability in RT SS, and overall ADHD SS (acomposite score of the previous submeasures).

The Primary outcome measure was the ADHD Score, TOVA Omission, TOVACommission, TOVA RT and TOVA Variability analysed as Standard Score in %compared to the patient's prior performance of the TOVA test atbaseline. Secondary outcome measures were Subtests from Weschler: Digitspan, Symbol Search, Digit symbol.

Results and Discussion:

As can be seen from Table 8, a significant improvement is manifested inthe ADHD score, RT Time and RT variability, (which are considered to bemore sensitive parameters in the adult population), at all time pointsafter baseline, with 4 hrs showing the maximal outcome. It is noted thatcommission results showed improvement even after 90 minutes from dosing.It is further noted that after 7 hrs from dosing improvement wasdiminished, however showed improved results compared to baseline.

TABLE 8 Baseline 90 min 4 hr 7 hr ADHD Score −3.79 −0.34 0.85 0.04Omission 91.8 84.3 93.3 88.1 Commission 108.2 103.6 98.6 102.4 RT Time92.3 110 113.1 112.3 RT Variability 92.625 101.9 106 100.2

Example 4 Effects of Metadoxine on Cognitive Performance of SleepDeprived Subjects

The double-blind study compared the cognitive performance of 14 healthyadults (ages 18-40) using cognitive tasks following a 24-hour period oftotal sleep deprivation (TSD).

Standardized neuropsychological testing was conducted in cognitivedomains which have previously been shown to be affected by sleep and/orsleep deprivation, such as processing speed, attention, and inhibition.

All participants wore an actigraph for one week prior to study onset andfor the duration of the study to document sleep-wake behavior.

Each participant was administered with one of two counterbalancedtreatment conditions: (1) Composition of the invention (single dose 1400mg DER Metadoxine) or (2) Placebo.

Procedures

a. Sleep Protocols:

On the day of the study, participants were instructed to:

-   -   1. Wake up no later than 08:00 (at home).    -   2. Not to nap for the duration of the day and refrain from any        alcohol or stimulant use.    -   3. Arrive at the sleep laboratory at 20:00.    -   4. Remain awake for the duration of the night (with        supervision).    -   5. Refrain from consumption of any food or liquids starting at        05:00.    -   6. At 07:00 the following morning, participants received either        a composition of the invention or placebo from the study        physician or licensed nurse dedicated to the study.    -   7. Participant performed cognitive tasks at 08:30 (task        duration: 30 minutes).        b. Actigraphy.

An actigraph is a small, light device (˜size of a wrist watch), placedon the subject's non-dominant wrist, which contains a movement sensor(accelerometer) that collects physical movement data sampled severaltimes per second and stored in 1-minute epochs. Sleep/wake patterns weremonitored using actigraphy, which has been validated againstpolysomnography, resulting in high correlations on sleep measures.Participants continuously wear an actigraph starting one week before theexperimental phase until the end of the active protocol. Actigraphs arewaterproof and durable and attached using non-removable wristbands, toensure they are worn continuously.

c. Neuropsychological Testing.

Digit Symbol Substitution Test (DSST) (WAIS-III) is a paper-and-pencilprocessing speed task that measures visual-motor coordination andprocessing speed. It consists of nine digit-symbol pairs followed by alist of digits. Under each digit the subject is asked to write down thecorresponding symbol as quickly as possible. The number of correctsymbols within the allowed time (120 seconds) is measured.

Connors' Continuous Performance Task (CPT; www.bdikalkeshev.co.il,Tel-Aviv University)) is a computerized task that covers cognitivedomains reported to be affected by sleep or sleep loss, includingprocessing speed, attention, and inhibition. Different figures areflashed sequentially on a computer screen and participants areinstructed to respond to certain figures as quickly as possible (usingkeyboard), while inhibiting other figures (i.e. no responding). Thistask takes approximately 17 minutes to complete.

Digit Span (WA IS-III) is a test of attention, concentration, andworking memory. Subjects are given sets of digits to repeat initiallyforwards then backwards. The task takes approximately 5 minutes tocomplete.

Paced Auditory Serial Addition Task—3rd Edition (PASAT-III) is acomputerized task that measures auditory information processing speedand flexibility, as well as working memory. Single digits are presentedeither every 3 seconds (trial 1) or every 2 seconds (trial 2), and thepatient must add each new digit to the one immediately prior to it. ThePASAT is presented on compact disk to control the rate of stimuluspresentation. The test score is the total number of correct sums given(out of 60 possible) in each trial. This task takes approximately 8minutes to complete.

The tests were performed by a trained staff and took approximately 45minutes to complete.

At the end of each cognitive testing session, the Karolinska SleepinessScale (KSS: 9-point anchored scale) was administered, together with aseries of 10-point Likert scales asking about motivation to performwell, ability to concentrate, amount of effort required to perform thetask, and perceived task difficulty. The Likert questions are useful inexamining whether performance is related to subjective effort, taskdifficulty, or sleepiness.

Results and Discussion

Results show clear trends of the efficacy of DER Metadoxine treatmentover placebo treatment. Table 8 shows the significance of difference(delta) between Placebo and Drug outcomes:

TABLE 8 N Mean Std Dev Minimum Median Maximum Pr > |t| CPT Omission (RawScore) 14 3.86 9.19 −2.00 0.00 34.00 0.07 CPT Reaction Time StandardDeviation 14 1.64 3.91 −3.01 0.20 12.10 0.07 CPT Variability 14 6.4113.64 −4.37 0.48 43.52 0.05

Example 5 Metadoxine Formulation for Improvement of CognitivePerformance of Elderly Subjects

Twenty five patients of 60-79 years suffering from mild cognitiveimpairment (MC1) perform computerized neuropsychological test(Mindstreams) at the beginning of the study—(control 1), following 1week administration of 350 mg metadoxine formulation twice a day (test1), following 1 week wash-out period (control 2) and following 1 weekadministration of placebo formulation (test 2).

The results are analyzed for differences between control and test. Animprovement in some parameters like: digit recall, pattern recall withdrug compared to placebo is expected.

Example 6 Metadoxine Formulation for Improvement of CognitivePerformance of Tired Subjects

Twenty physicians, following 30 hours without any sleep, perform Ray'smemory test at the beginning of the study—control (baseline of study)and 1 hour after administration of metadoxine formulation-test.

The results are analyzed for differences between control and test. Animprovement in some parameters like: number of remembered words withdrug is expected in the treated group compared to control.

Example 7 Metadoxine Formulation for Improvement of CognitivePerformance of Alzheimer's Disease (AD) Patients

Twenty AD patients perform memory test at the beginning of thestudy—control (baseline of study) and after 1 month administration ofmetadoxine formulation. The results are analyzed for differences betweencontrol and test. An improvement in some parameters like: digit recallwith drug compared to control is expected.

Example 8 Metadoxine Formulation for Improvement of CognitivePerformance of Multiple Sclerosis Disease (MS) Patients

Twenty MS patients perform memory test at the beginning of thestudy—control (baseline of study) and after 1 month administration ofmetadoxine formulation.

The results are analyzed for differences between control and test. Animprovement in some parameters like: digit recall with drug compared tocontrol is expected.

Example 9 Metadoxine Formulation for Treatment of SWSD (Shift Work SleepDisorder)

Sixty volunteers with chronic SWSD are divided into two groups:volunteers of one receive Metadoxine 700 mg SR capsules, and those ofthe second group receive placebo capsules. Both groups are tested for:Psychomotor Vigilance Task (10 minute visual sustained-attention testthat is sensitive to sleepiness), Continuous Performance test (CPT-14minutes computer vigilance task) and Simulated Driving Task (20 minutesdriving task sensitive to sleepiness which runs on a computer withsoftware, steering wheel, accelerator and brake). Tests are performed atbaseline and after treatment.

The results of measured parameters like: reaction time, commissions,omissions, lane variability, and speed variability are analyzed. Betterresults are expected for the group receiving Metadoxine.

Example 10 Comparative Dissolution Test: Immediate Release Vs. SlowRelease

Immediate release tablets were prepared using high shear wet granulationtechnology according to the following composition:

Metadoxine 500 milligrams  Avicel PH 101 ™ 72 milligrams PVP K-30 28milligrams Magnesium stearate  5 milligrams

Slow release tablets were prepared using high shear wet granulationtechnology according to the following composition:

Metadoxine 455 milligrams Metholose 90SH 152 milligrams Ethocel E10 ™ 25 miligrams Aerosil 200  5 milligrams Magnesium stearate  7 milligrams

Dissolution was tested using USP Apparatus 2 (paddles), 50 xrpm, in 500ml intestinal fluid pH=6.8, 37° C. Comparative dissolution results arepresented in FIG. 2. The immediate release formulation released morethan 90% in 0.5 hour, while slow release tablets released about 70% over8 hours.

Example 11 Slow Release Capsules of Metadoxine

Granules were prepared using high shear granulation and vacuum drying.This is an example of an acrylic hydrophobic polymer as a polymericmaterial.

Metadoxine 350 milligrams per capsule  Calcium carbonate 45 milligramsper capsule Eudragit RS ™ 60 milligrams per capsule

Materials were mixed together and granulated with a Eudragit RS™solution in ethanol. Granules were filled into gelatin capsules.

Example 12 Controlled Release Syrup of Metadoxine

Syrup is prepared using an overhead rotary mixer.

Metadoxine granules 700 milligrams per 5 milliliters Cherry flavor 10milligrams per 5 milliliters Xylitol solution ad. 5 milliliters volume

Metadoxine slow release granules (from Example 8) are mixed in xylitolsolution. Cherry flavor is added.

Example 13 Ready-to-Swallow Sachets of Metadoxine

Two granulations are performed in a mixer granulator:

Granules No. 1: Metadoxine 500 milligrams  PVP K-25 10 milligramsGranules No 2: Metadoxine 800 milligrams  Metholose 90SH 200 milligrams Ethocel E10 ™ 50 milligrams Final Mix: Magnesium stearate 10 milligramsAerosil 200 ™  5 milligrams Strawberry flavor 10 milligrams

Granules No 1 (immediate absorption formula) and Granules No 2 (slowrelease formula) are mixed together with other ingredients and filledinto sachets.

Example 14 Dermal Patch of Metadoxine

Materials (below) are mixed together to form a clear gel. The gel iscoated onto a backing membrane by using coating equipment. The laminateis dried and a polyester release liner is laminated onto the driedmetadoxine gel. The sheet is cut into patches and stored in a coolplace.

Metadoxine 2500 milligrams Durotak 387-2287 200 milligrams Ethanol 10milliliters Water 5 milliliters

Example 15 Metadoxine Effervescent Powder

Micro granules (pellets) are prepared using extrusion technology:

Metadoxine 100 milligrams Metholose 90SH  35 milligrams Pellets aremixed with Metadoxine 200 milligrams Sodium bicarbonate  60 milligramsCitric acid 100 milligrams Sucralose  20 milligrams Cherry flavor  10milligrams The mixture is filled into sachets.

1-16. (canceled)
 17. A method of treatment, alleviation of symptoms of,relieving, improving and preventing a cognitive disease, disorder orcondition in a subject, comprising administering to said subject atherapeutically effective amount of a salt adduct comprising at leastone positively charged moiety being a pyridoxine or a derivative thereofand at least one carboxylated 5- to 7-membered lactam ring, optionallyadditionally substituted.
 18. A method of improving cognitive functionsin a healthy subject comprising administering to said subject aneffective amount of a salt adduct comprising at least one positivelycharged moiety being a pyridoxine or a derivative thereof and at leastone carboxylated 5- to 7-membered lactam ring, optionally additionallysubstituted.
 19. A method according to claim 17 or claim 18, whereinsaid positively charged moiety is a compound of formula (I):

wherein R₁ is straight or branched C₁-C₆ alkyl; R₂ is selected from —OH,straight or branched C₁-C₆ alkoxy, and straight or branched C₁-C₆alkoxycarbonyl; R₃ and R₄ are each independently selected from formyl,straight or branched C₁-C₆ alkyl optionally substituted by at least onehalogen, amine, hydroxy, C₁-C₆ alkoxy, thiol and C₁-C₆ alkoxycarbonyl.20. A method according to claim 17 or claim 18, wherein saidcarboxylated lactam ring is selected from the group consisting of:

wherein R₆ is selected from H, straight or branched C₁-C₆ alkyloptionally substituted by at least one halogen, straight or branchedC₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl, cycloalkyl, aryl andheteroaryl optionally substituted by a C₁-C₆ alkyl; R₇, R₈, R₉, R₁₀ R₁₁,R₁₂, R₁₃ and R₁₄ are each independently selected from H, straight orbranched C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, aryl andheteroaryl optionally substituted by at least one group selected fromC₁-C₆ alkyl, halogen, amino, cyano, nitro, thiol, C₁-C₆ alkoxy,aminocarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ carboxyalkyl, C₁-C₆alkoxycarbonylalkyl and amidino.
 21. A method according to claim 17 orclaim 18, wherein said salt adduct is selected from the following:


22. A method according to claim 17, wherein said cognitive disease,disorder or condition is selected from Attention Deficit/HyperactivityDisorder (ADHD/ADD), impaired memory (Amnesia), impaired wakefulness,mental fatigue conditions, Shift Work Sleep Disorder, Narcolepsy,Obstructive Sleep Apnea/Hypopnea Syndrome, poor concentration, and poorfocus or any combination thereof.
 23. A method according to claim 17,wherein said cognitive disease, disorder or condition is selected fromlearning disabilities, impairment of memory, cognitive dysfunction,alteration of cognitive function, including Alzheimer's disease, or anytype of encephalopathy, including uremic and hepatic encephalopathy. 24.A method according to claim 17, wherein said cognitive disease, disorderor condition is a neurobehavioral disease, disorder or condition.
 25. Amethod according to claim 17, wherein said cognitive disease, disorderor condition is a neurobehavioral disease, disorder or conditionselected from Attention Deficit Hyperactivity Disorder (ADHD), AttentionDeficit Disorder (ADD), impaired memory, poor concentration, and poorfocus.
 26. A method according to claim 17, wherein said cognitivedisease, disorder or condition is selected from Attention DeficitDisorder (ADD) or Hyperactivity Disorder (ADHD/ADD), impaired memory(Amnesia), impaired wakefulness, mental fatigue conditions, Shift WorkSleep Disorder, Narcolepsy, Obstructive Sleep Apnea/Hypopnea Syndrome,poor concentration, and poor focus or any combination thereof.
 27. Amethod according to claim 18, wherein said cognitive function selectedfrom temporary or long term learning disabilities, temporary or longterm impairment of memory, temporary or long term cognitive dysfunction,temporary or long term alteration of cognitive function, temporary orlong term concentration impairment, temporary or long term focusimpairment, temporary or long term impaired wakefulness, temporary orlong term mental fatigue conditions, temporary or long term Shift WorkSleep Disorder, or any combination thereof.
 28. A method according toany one of claims 17 and 18, wherein said subject is a child, anadolescent, an adult, or an elderly person.
 29. A method according toany one of claims 17 and 18, wherein said salt adduct is formulated in asustained-, delayed or controlled-release dosage form.
 30. A methodaccording to any one of claims 17 and 18, wherein said salt adduct isformulated in a sustained-, delayed or controlled-release dosage formcombined with a salt adduct formulated in an immediate or burst effectdosage form.
 31. A method according to any one of claims 17 and 18,wherein said salt adduct is formulated to deliver up to 0.1-1000 mg/kgbody weight/day of said salt adduct, preferably 1-400 mg/kg body weightof said salt adduct, in a single dose administration or portion thereof.32. A method according to any one of claims 17 and 18, wherein said saltadduct is formulated together with at least one additionalpharmaceutically active agent.